Sjogren's Syndrome (SS) is the most common idiopathic cause of xerostomia and concomitant gingivitis and dental caries in postmenopausal women. The long term objectives of this proposal are to determine definitively the role of Epstein-Barr virus (EBV) in mediating the oral immunopathology of SS. This objective will be accomplished by a unique team of investigators with extensive expertise in several distinctly relevant areas including 1) the histologic and immunopathologic manifestations of SS in the minor salivary glands, 2) the ocular manifestations of human SS, 3) the immunopathogenesis of murine models of 55, 4) the molecular biology of EBV and its receptor CR2 (CD21), and 5) the cellular and molecular biology of T lymphocyte responses to viral infections. EBV, an oncogenic herpesvirus, is unique in its capacity to infect B lymphocytes and oropharyngeal epithelia in greater than 90% of humans by adulthood, after which it escapes immune surveillance and is harbored in a benign, latent state. However, during states of immune suppression such as acquired immunodeficiency syndrome (AIDS), post-transplant chemotherapy, and malaria, the oncogenic potential of EBV is unleashed in the form of malignant outgrowth of B cells such as in Burkitt's lymphoma. Similarly, aberrant immune regulation of EBV-infected oral epithelia is intimately associated with the development of nasopharyngeal carcinoma and oral hairy leukoplakia. These and several additional observations have suggested that impaired regulation of EBV infected cells is also involved in both the salivary gland destruction and the susceptibility to B cell lymphomas that are characteristic of 55. However, the molecular basis for EBV tropism for oral epithelia, the normal immune response to this virus, and differences in the life cycle of EBV harbored within epithelium vs. within B lymphocytes remain unclear, and these obstacles have impaired progress in defining the role of this pathogen in 55. The goals of this proposal are to 1) determine the role for human CR2 in mediating viral infection of human oral epithelia, 2) determine the genotype of EBV strains and the state of viral activation within minor salivary glands, lacrimal glands, and peripheral blood of patients with Sjogren's Syndrome, and 3) determine whether the T cell infiltrates within salivary glands of patients with Sjogren's syndrome are targeted to EBV-encoded antigens.